Is ACVR1C p.Ile355Val (c.1063A>G) pathogenic?

ACVR1C p.Ile355Val (c.1063A>G) is classified Uncertain significance in ACVR1C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-21). AlphaMissense: likely benign (0.0737); Rare (popmax 0.462%, mid).

How common is ACVR1C p.Ile355Val (c.1063A>G) in the general population?

ACVR1C p.Ile355Val (c.1063A>G) is rare (popmax 0.462%, mid) (gnomAD).

What do computational predictors say about ACVR1C p.Ile355Val (c.1063A>G)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

ACVR1C p.Ile355Val

c.1063A>G · rs35500979 · VCV2384807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.71, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 95 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.462% Middle Eastern · 28/6,060 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.283%

Overall 0.0126% 204/1,613,926 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.462%	216
South Asian	0.0626%	1,597
Remaining individualsnot grpmax-eligible	0.0432%	2,315
African / African-American	0.0267%	3,752
Admixed American	0.0183%	5,453
East Asian	0.0134%	7,474
European (non-Finnish)	0.00458%	21,850
Finnishnot grpmax-eligible	0.00156%	64,042

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACVR1C
Protein: p.Ile355Val
Coding: c.1063A>G
MANE Select: NM_145259
dbSNP: rs35500979
Type: single nucleotide variant
Location: chr2:157542743 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.35
Residue 355: a UniProt-annotated variant site (in); the protein kinase domain

Full ACVR1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR1C c.1226-50T>C Benign ★★ same type
ACVR1C c.1356+6G>C Benign ★★ same type
ACVR1C c.305-34T>C Benign ★★ same type
ACVR1C c.544+63A>G Benign ★★ same type
ACVR1C c.73+9C>A Benign ★★ same type
ACVR1C c.776-13A>G Benign ★★ same type
ACVR1C c.943+49G>A Benign ★★ same type
ACVR1C p.Asn150His Benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/acvr1c-p-ile355val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown